PROJECT SUMMARY Up to 60% of patients with Alzheimer?s disease (AD) exhibit seizures and network hyperactivity, leading to a faster cognitive decline. Therefore, seizures in AD should be an important focus for therapeutic interventions. The microtubule-associated protein tau, a central factor in AD pathogenesis, mediates seizures and associated memory loss in models of AD, suggesting that targeting tau could effectively treat seizures in AD. However, there is a fundamental gap in understanding how tau contributes to seizures in these models. Broadly reducing tau levels successfully prevents seizures; however, reducing tau also causes deleterious effects in aged mice and the safety of this approach in the adult human brain is unknown. Therefore, a better understanding of how tau contributes to seizures is needed in order to develop more precise therapies targeting tau. The overall objective here is to identify a mechanism by which tau mediates seizures and related functional deficits in mouse models of AD and genetic epilepsy. The applicant has obtained preliminary data indicating that blocking tau?s interactions with SRC Homology 3 (SH3)-containing proteins can prevent seizures and associated memory loss in AD. The central hypothesis, based on the applicant?s preliminary data, is that tau binds to SH3-containing enzymes on its proline-rich region, and regulates network activity by modulating the activity or cellular localization of these enzymes. Previous studies, supportive of this concept, have indicated that binding between tau and the tyrosine kinase Fyn, which regulates excitatory receptors, are involved in tau?s ability to regulate seizures. The applicant?s preliminary data expands on these findings to indicate additional SH3-containing enzymes that bind tau and are involved in this phenomenon. The rationale for the proposed research is that, once it is known which enzymes are important for tau?s ability to mediate seizures, tau?s binding affinity with these enzymes can be manipulated pharmacologically, resulting in new and innovative approaches to the prevention and treatment of seizures and associated memory loss in AD. Guided by strong preliminary data in which the applicant created two novel mutant tau knockin mouse models, this hypothesis will be tested by pursuing two specific aims: 1) Determine the influence of variants in the proline-rich region of tau that prevent its binding to SH3-containing enzymes on signal transduction initiated by A? oligomers, which are epileptogenic peptides linked to AD, and excitotoxins, and 2) Determine the extent to which these variants in tau prevent seizures, behavioral deficits, and premature mortality in mouse models of AD and genetic epilepsy. The proposed research is innovative because it represents a substantive departure from the status quo by shifting focus to tau?s upstream modulation of cell signaling related to A? and excitotoxicity. This contribution is expected to be significant because it will have broad translational importance in the prevention and treatment of seizures and associated memory loss in AD.